scholarly journals Long-term and acute safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) in juvenile and adult dogs

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kari L. Riggs ◽  
Scott Wiseman
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Clinical Pathology ◽  
Control Group ◽  
Combination Drug ◽  
Milbemycin Oxime ◽  
Safety Studies ◽  
Chewable Tablets ◽  
Long Term Studies

Abstract Background The combination of milbemycin oxime (MO) and lotilaner (Credelio® Plus) is a novel systemic endectocide that provides month-long effectiveness in dogs after a single oral treatment. The safety of Credelio® Plus flavored chewable tablets was investigated in three target animal safety studies. Two studies (one in juveniles and one in adults) evaluated the long-term safety, and one study evaluated the acute safety of the product when administered orally at the upper end of the recommended dose range (0.75–1.53 mg/kg MO and 20–41 mg/kg lotilaner) and multiples of this dose. Methods The objectives of these studies were to determine the long-term and acute safety of MO and lotilaner flavored chewable tablets in healthy dogs. All three studies were randomized, blinded, parallel-group design studies in healthy Beagle dogs. In each of the two long-term studies, 32 dogs were randomized among four groups to untreated controls or to treated groups at target doses of 1X, 3X, or 5X. Treatment was administered on seven (adult dogs) or nine (juvenile dogs) occasions with dosing every 4 weeks. In the acute study, 48 dogs were randomized among four groups to untreated controls or to treated groups at 1X, 3X, or 6X. In all three studies, the control group was administered placebo tablets. All dogs were fed 30 to 45 min prior to treatment and the assessment of safety was based on health observations, complete physical/neurological examinations, and food consumption. For the long-term safety studies, safety assessments also included clinical pathology evaluations (hematology, clinical chemistry and urinalysis), body weight, pharmacokinetic blood collections, and macroscopic and microscopic examinations of collected tissues. Results MO and lotilaner did not induce any treatment-related adverse effects based on health observations, physical/neurological examinations, or food consumption in the long-term or acute studies. Additionally, in the long-term studies, MO and lotilaner did not induce any treatment-related effects on clinical pathology, body weight, and macroscopic and microscopic examinations. Conclusions These three studies demonstrate that Credelio® Plus has a wide safety margin when administered at monthly intervals to puppies and dogs at the high end of the commercial dose band. Graphic Abstract

scholarly journals Acute and Long-Term Toxicity of Mango Leaves Extract in Mice and Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yi Zhang ◽  
Jian Li ◽  
Zhizhen Wu ◽  
Erwei Liu ◽  
Pingping Shi ◽  
...  
Keyword(s):  
Body Weight ◽  
Female Rats ◽  
Male Rats ◽  
Control Group ◽  
Maximal Dose ◽  
Sd Rats ◽  
Body Weight Increase ◽  
Mango Leaves ◽  
Long Term Studies

The acute toxicity of mango leaves extract (MLE) at the maximal dose (18.4 g/kg) was studied in ICR mice and no abnormalities were detected during the experiment. The long-term studies at various doses of MLE (100 mg/kg, 300 mg/kg, and 900 mg/kg) in SD rats for 3 consecutive months revealed that, compared with the control group, rats in MLE treated groups showed slight body weight increase and higher fat weight; the serum TG and CHOL levels and the epididymis weight of male rats were a little higher; the serum K+level of female rats was on the low side but the weights of liver, kidney, and adrenal gland were on the high side. In addition to this, no other obvious abnormalities were detected.

Lack of Oncogenicity of Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medication, in Sprague-Dawley Rats

2001 ◽  
Vol 20 (5) ◽  
pp. 297-305 ◽  
Author(s):  
Tomoo Kuge ◽  
Takashi Shibata ◽  
Michael S. Willett ◽  
Patricia Turck ◽  
Karl A. Traul
Keyword(s):  
Body Weight ◽  
Dose Level ◽  
Active Ingredient ◽  
Clinical Signs ◽  
Clinical Pathology ◽  
Maximum Tolerated Dose ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Wood Creosote

Seirogan, an herbal medicine containing wood creosote (tablets, 10.0% w/w), has been developed and marketed for almost a century in various countries for the control of acute diarrhea and treatment of associated symptoms, such as abdominal cramping. Wood creosote (CAS no. 8021–39–4) is a mixture of simple phenolic compounds, including guaiacol and creosol and related compounds, and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. In the current study, the oncogenic potential of wood creosote was assessed in a 96/103-week oral gavage study in Sprague-Dawley rats. Groups of 60 rats/sex received wood creosote at dose levels of 20, 50, or 200 mg/kg body weight [bw]/day. An additional group of rats received the vehicle, 0.5% carboxymethylcellulose in deionized, distilled water, at the same dose volume as the treatment groups (10 ml/kg) and served as the controls. Treatment-related decreases in survival, body weight, and food consumption, as well as increased incidences of clinical signs that included rales, decreased activity, and salivation, were noted at 200 mg/kg bw/day when compared with the control group. There was an increased incidence of reddened and edematous lungs in rats from the 200 mg/kg bw/day group that died during the study. The lung findings were suggestive of test article aspiration during dose administration or agonal aspiration preceding and possibly resulting in death, especially because these observations were not seen in animals that survived to scheduled sacrifice. Additionally, phenols are generally recognized as having corrosive properties. There were no changes in clinical pathology and no increases in neoplastic or non-neoplastic lesions, excluding the lung findings, related to treatment with wood creosote at any dose level. Although the results of this study indicate that the maximum tolerated dose of wood creosote was met or exceeded at 200 mg/kg bw/day, there was no evidence of oncogenicity at any dose level. The lack of any evidence of oncogenicity supports the safety profile of the active ingredient in Seirogan, wood creosote.

scholarly journals Effects of long-term GH-releasing factor administration on patterns of GH and LH secretion in growing female buffaloes (Bubalus bubalis)

Reproduction ◽  
2004 ◽  
Vol 127 (1) ◽  
pp. 45-55 ◽  
Author(s):  
M Mondal ◽  
B S Prakash
Keyword(s):  
Body Weight ◽  
Treatment Group ◽  
Bubalus Bubalis ◽  
Saline Control ◽  
Control Group ◽  
Post Injection ◽  
Long Term Treatment ◽  
Plasma Gh ◽  
Lh Secretion

To investigate the effects of long-term GH-releasing factor (GRF) administration on the patterns of GH and LH secretion in growing female Murrah buffalo (Bubalus bubalis) calves, 12 buffaloes of 6–8 months of age were divided into two groups (treatment and control groups) of six each in such a way that average body weight between the groups did not differ significantly (P > 0.05). Both the groups were administered i.v. with either synthetic bovine GRF (bGRF(1–44)-NH2) at 10 μg/100 kg body weight (treatment group) or an equal volume of normal saline (control group) at intervals of 15 days until 18 injections had been completed (9 months). Blood samples collected prior to and after the first and last injection of GRF at −60, −45, −30, −15, −10, −5 min and +5, +10, +15, +30 min, and thereafter at intervals of 15 min up to 8 h post-injection, were assayed for plasma GH and LH. Plasma progesterone was also estimated in twice-a-week samples to assess whether either group had begun ovarian cyclicity. The body weight of all animals was recorded twice a week. In all animals, a peak of GH was recorded within 5–20 min and 5–30 min after the first and last GRF injections and post-injection mean values for plasma GH were significantly (P < 0.01) higher compared with the control group of animals. Although peak GH values after the first and last GRF injection did not differ (P > 0.05), GH levels were maintained at a higher level for a longer time after the last GRF injection compared with the first (240 vs 150 min). The area under the GH response curve after the last GRF injection was found to be significantly (P < 0.01) higher than after the first injection (9344 ± 99.7 vs 7763 ± 112.4 ng/ml × min). The mean post-injection plasma LH levels of the treatment group were significantly (P < 0.01) higher after both the first and last GRF injections than in the control group of animals. Interestingly, compared with the first GRF injection, the pre-injection plasma LH level was found to be significantly higher (P < 0.01) at the last injection. The plasma LH concentrations around the last injection of GRF were significantly higher (P < 0.01) than those recorded at the time of the first injection in treated buffaloes. Correspondingly, the plasma LH concentrations in controls were also higher (P < 0.01) around the last injection of GRF vis-à-vis the first injection. The hormone concentration exhibited a higher pulsatility with greater amplitude after the last injection as compared with that recorded after the first injection. Although pulses of LH were also recorded in controls following the last injection, these were fewer and of lower magnitude than those seen in treated animals. No animal from either group reached puberty. GRF-treated buffaloes attained higher (P < 0.001) body weight than the controls. In conclusion, long-term administration of GRF induces and even enhances GH release without any sign of refractoriness, and significantly increases plasma LH also. Hence, long-term treatment with GRF may be used to maintain a sustained increased level of plasma GH in buffaloes and it may assist the animals of this species to grow faster.

scholarly journals Efficacy of milbemycin oxime/afoxolaner chewable tablets (NEXGARD SPECTRA®) against Capillaria aerophila and Capillaria boehmi in naturally infected dogs

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Angela Di Cesare ◽  
Simone Morelli ◽  
Giulia Morganti ◽  
Giulia Simonato ◽  
Fabrizia Veronesi ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Anthelmintic Activity ◽  
Oral Formulation ◽  
Negative Control ◽  
Control Group ◽  
Milbemycin Oxime ◽  
Chewable Tablets ◽  
Capillaria Aerophila ◽  
Group 2 ◽  
Capillaria Boehmi

Abstract Background Capillaria aerophila and Capillaria boehmi parasitize the respiratory system of wild and domestic carnivores. Capillaria aerophila inhabits the trachea and bronchi of dogs and cats, while C. boehmi affects the nasal cavities and sinuses of dogs. In dogs the infection may be subclinical or characterized by varying respiratory distress. Methods The present study evaluated the efficacy of an oral formulation containing milbemycin oxime and afoxolaner (NEXGARD SPECTRA®) in dogs naturally infected with C. aerophila and/or C. boehmi from three enzootic areas of Italy. Dogs were enrolled pending fecal examination and molecular confirmation of respiratory capillarioses. Dogs were allocated in two groups: Group 1 (G1, 25 dogs), treated with a negative control product with no anthelmintic activity (afoxolaner, NEXGARD®), and Group 2 (G2, 26 dogs), treated with NEXGARD SPECTRA®. At the day of treatment administration (Day 0), all dogs were clinically examined. Dogs were again subjected to clinical and fecal examinations at Days 28 (± 4) and 56 (± 2). The primary criterion for treatment efficacy was the reduction of fecal Capillaria egg counts in G2 compared with G1. The regression of/recovery from baseline clinical signs was considered as a further efficacy criterion. Results Percentage reduction of fecal Capillaria egg counts in the NEXGARD SPECTRA® group compared to the control group was > 97% on Day 28 and 100% on Day 56, respectively (p < 0.05 for both time points). Twelve of the 13 dogs in the NEXGARD SPECTRA® group with respiratory signs prior to treatment were free of clinical signs at the end of the study. Conversely, the six control group dogs with respiratory signs prior to treatment remained symptomatic. Conclusions Results of the present study showed that NEXGARD SPECTRA® was safe and highly efficacious in the reduction of C. aerophila and C. boehmi eggs after one treatment with a complete reduction of the egg output after the second administration associated with a recovery from respiratory signs.

scholarly journals Effects of Cimetidine on Broiler Fattening and on Stress-Induced Gizzard Erosion in Chicken

1999 ◽  
Vol 47 (2) ◽  
pp. 233-241 ◽  
Author(s):  
Ž. Grabarević ◽  
P. Džaja ◽  
J. Perić ◽  
V. Šerman ◽  
Z. Biđin ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Morphometric Analysis ◽  
Tap Water ◽  
Water Immersion ◽  
Carcass Weight ◽  
Feed Consumption ◽  
Control Group ◽  
Feed Deprivation

The work describes the effects of cimetidine on stress-induced gizzard erosions (Experiment A) and the influence of the long-term application (42 days) of the same drug on weight gain and feed consumption during broiler fattening (Experiment B). For Experiment A, 60 male, three-day-old chicks were divided into two groups: C (n = 30) - control chicks treated with 0.5 ml saline; CIM (n = 30) - chicks treated with cimetidine in a dose of 5 mg/kg body weight (b. w.) in-tragastrically. All chicks were stressed using a modified water-immersion stress method according to which the chicks, after 24 h of feed deprivation, were immersed in tap water (17 °C) for a few seconds. Under chloroform anaesthesia ten chicks from each group were killed 1, 2 and 3 h after the stressing. The morphometric analysis of gizzard erosion (GE) and histopathological examinations of gizzards were performed for each chick. In Experiment B, 32 one-day-old broilers of both sexes were used. The control group was untreated (n = 16) while the CIM group (n = 16) was fed the same diet supplemented with 10 mg of cimetidine per kilogram of feed throughout the fattening period (42 days). The results of Experiment A showed decreased mean length of the GE in the cimetidine-treated birds as compared with the GE lesions of the controls. In Experiment B, the treated chicks had reduced liveweight (1835.1 g), carcass weight (1474.6 g) and increased feed consumption (2115 g of feed per kilogram of weight gain) compared to the controls in which the same parameters were 1898.5 g, 1574.2 g and 1797 g, respectively. The results show that while stress-induced GE of chicks can be medicated pharmacologically, long-term application of the same substance impairs the results of fattening.

The effects of underfeeding for 6 months during pregnancy and lactation on blood constituents, milk yield and body weight of dairy cows

1978 ◽  
Vol 90 (2) ◽  
pp. 383-394 ◽  
Author(s):  
C. J. Roberts ◽  
I. M. Reid ◽  
Sally M. Dew ◽  
A. J. Stark ◽  
G. D. Baird ◽  
...  
Keyword(s):  
Body Weight ◽  
Dairy Cattle ◽  
Milk Yield ◽  
Control Level ◽  
Energy Deficit ◽  
Control Group ◽  
Blood Constituents ◽  
Pregnancy And Lactation ◽  
Cattle Husbandry

SummaryLong-term undernutritional stress is often a feature of sheep and beef cattle production, but has only become a major feature of dairy cattle husbandry in the United Kingdom in recent winters when food was short and expensive. An experiment was carried out to study the effects of long-term underfeeding during pregnancy and early lactation on some blood constituents, milk yield and composition and body weight of dairy cattle. Two groups of cattle were fed at 60 and 40% of the estimated requirements for maintenance and pregnancy or lactation for 13 weeks before and 13 weeks after calving, and one group was fed at the maintenance level only for the same period. A control group was fed at 100% of estimated requirements for this period. All groups were subsequently fed at the control level for a further 24 weeks.The experiment showed that cows undergoing long-term nutritional deprivation were able to maintain concentrations of blood constituents within narrow limits; the concentrations of such constituents as glucose or non-esterifled fatty acid did not reflect energy deficit or surplus. The animals remained clinically healthy during the underfeeding and recovery periods. The results suggest that debility occurring under field conditions in association with reduced food supply may be due to a multiplicity of factors or to severe imbalance of specific nutrients, rather than to energy or protein deficit alone.There was a difference in efficiency of utilization of energy of 19% between cows in the most severely underfed groups which maintained lactation and those which were not able to maintain lactation. There was evidence that this difference in efficiency was detectable within a few weeks of the start of the period of reduced nutrition. Animals which were less affected in the early stages of food deprivation were also those which maintained the advantage through the deprivation and recovery periods.

scholarly journals Safety evaluation of the interchangeable use of robenacoxib in commercially-available tablets and solution for injection in cats

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Mark C. Heit ◽  
L. Jay Stallons ◽  
Wolfgang Seewald ◽  
Caryn M Thompson ◽  
Céline E. Toutain ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Day Treatment ◽  
Oral Treatment ◽  
Subcutaneous Administration ◽  
Systemic Exposure ◽  
Control Group ◽  
Serious Adverse Events ◽  
Blood Concentrations ◽  
Daily Dose

Abstract Background Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation. Results Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib. Conclusions This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

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